US9120810B2ActiveUtilityA1
Compounds and methods for the treatment of isocitrate dehydrogenase related diseases
Est. expiryMar 29, 2031(~4.7 yrs left)· nominal 20-yr term from priority
Inventors:Mahmud M. HussainDaisuke ItoJason LawMatthias LeiendeckerKe LiuBenito MunozStuart L. SchreiberAlykhan ShamjiAndrew M. Stern
C07D 413/14C07D 417/14C07D 417/12A61P 35/00C07D 419/12C07D 498/04C07D 413/12
78
PatentIndex Score
2
Cited by
10
References
47
Claims
Abstract
The invention relates to compounds of Formula I or a pharmaceutically acceptable salt, ester or prodrug thereof:
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1. A compound of Formula IA, IB, IC or ID, or a pharmaceutically acceptable salt, ester or prodrug thereof:
wherein each n and m is independently 0, 1, 2 or 3;
each p and q is independently 0, 1, 2, 3, 4, 5, 6 or 7;
X 1 is —C(O)N(R A )— or —C(S)N(R A )—;
wherein R A is independently hydrogen, aliphatic, substituted aliphatic, heteroaryl, substituted heteroaryl, aryl or substituted aryl;
X 2 is —S— —O—, —S(O) 2 — —C(R 20 )(R 21 )— or —N(R B )—;
wherein R B is independently hydrogen, aliphatic, substituted aliphatic, heteroaryl, substituted heteroaryl, aryl or substituted aryl;
each R 1 and R 2 is independently hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl;
R 3 is hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl;
each R 10 , and R 28 is independently absent, hydrogen, halogen, —OR 20 , —SR 20 , —NR 20 R 21 , —CF 3 , —CN, —NO 2 , —N 3 , —C(O)OR 20 , —C(O)R 20 , —C(O)NR 20 R 21 , acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, aliphatic, substituted aliphatic, aryl or substituted aryl; alternatively two of R 10 groups together with the atoms to which they are attached and any intervening atoms may form an additional optionally substituted, 3, 4, 5, 6 or 7 membered ring;
wherein each R 20 and R 21 is independently hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl;
each R 11 is independently absent, hydrogen, halogen, —OR 20 , —SR 20 , —NR 20 R 21 , —CF 3 , —CN, —NO 2 , —N 3 , —C(O)R 20 , —C(O)OR 20 , —C(O)NR 20 R 21 , acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, aliphatic, substituted aliphatic, aryl or substituted aryl; alternatively two of R 11 groups together with the atoms to which they are attached and any intervening atoms may form an additional optionally substituted, 3, 4, 5, 6 or 7 membered ring;
each G 1 and G 2 is independently, absent, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl;
each R 27 and R 29 is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
wherein R 3a is selected from alkyl, aryl, alkyl substituted with aryl, straight chain or branched C 1 -C 10 alkyl, C 1 -C 10 alkenyl, C 1 -C 10 alkynyl, C 1 -C 10 alkoxy, alkoxyC 1 -C 10 alkoxy, C 1 -C 10 alkylamino, alkoxyC 1 -C 10 alkylamino, C 1 -C 10 alkylcarbonylamino, C 1 -C 10 alkylaminocarbonyl, aryloxyC 1 -C 10 alkoxy, aryloxyC 1 -C 10 alkylamino, aryloxyC 1 -C 10 alkylamino carbonyl, C 1 -C 10 -alkylaminoalkylaminocarbonyl, C 1 -C 10 alkyl(N-alkyl)aminoalkyl-aminocarbonyl, alkylaminoalkylamino, alkylcarbonylaminoalkylamino, alkyl(N-alkyl)aminoalkylamino, (N-alkyl)alkylcarbonylaminoalkylamino, alkylaminoalkyl, alkylaminoalkylaminoalkyl, alkylpiperazinoalkyl, piperazinoalkyl, alkylpiperazino, alkenylaryloxyC 1 -C 10 alkoxy, alkenylarylaminoC 1 -C 10 alkoxy, alkenylaryllalkylamino C 1 -C 10 alkoxy, alkenylaryloxyC 1 -C 10 alkylamino, alkenylaryloxyC 1 -C 10 alkylaminocarbonyl, piperazinoalkylaryl, heteroarylC 1 -C 10 alkyl, heteroarylC 1 -C 10 alkenyl, heteroarylC 1 -C 10 alkynyl, heteroarylC 1 -C 10 alkylamino, heteroarylC 1 -C 10 alkoxy, heteroaryloxyC 1 -C 10 alkyl, heteroaryloxyC 1 -C 10 alkenyl, heteroaryloxyC 2 -C 10 alkynyl, heteroaryloxyC 1 -C 10 alkylamino, and heteroaryloxyC 1 -C 10 alkoxy;
Cy1 is an optionally substituted aryl or optionally substituted heteroaryl; and,
R 40 is selected from:
wherein, R 41 is hydrogen, halogen, aliphatic, substituted aliphatic, aryl, substituted aryl, —OR 20 , —SR 20 , —NR 20 R 21 , —CF 3 , —CN, —NO 2 , —N 3 , —C(O)R 20 , —C(O)OR 20 , —C(O)NR 20 R 21 , acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl.
2. A compound of claim 1 having Formula IIA-IIIA or a pharmaceutically acceptable salt, ester or prodrug thereof:
wherein, n, p, q, X 2 , Cy1, R 1 , R 2 , R 3 , R 3a , R 10 , R 11 , and R 40 are as defined above.
3. A compound of claim 1 having Formula IVA or VA, or a pharmaceutically acceptable salt, ester or prodrug thereof:
wherein p, q, X 2 , R 1 , R 2 , R 3 , R 3a , R 10 , and R 11 are as defined above.
4. The compound according to claim 1 , wherein R 1 is an optionally substituted alkyl.
5. The compound according to claim 1 , wherein R 1 is an optionally substituted C 1 -C 6 alkyl.
6. A compound according to claim 1 , wherein Cy1 is selected from Table A:
TABLE A
wherein represents a single or double bond;
each R 12 is independently absent, hydrogen, —C(O)R 20 , —C(O)OR 20 , —C(O)NR 20 R 21 , acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, aliphatic, substituted aliphatic, aryl substituted aryl, heteroaryl or substituted heteroaryl;
d is 0, 1 or 2;
alternatively, two R 11 and R 12 groups may form an optionally substituted 3, 4, 5, 6, or 7 membered ring.
7. A compound according to claim 1 , wherein R 11 is selected from Table B:
TABLE B
wherein, t is 0, 1, 2, 3, 4, 5, 6 or 7;
Cy2 is an optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl,
each R 13 , R 14 and R 15 is independently absent, hydrogen, halogen, —OR 20 , —SR 20 , —NR 20 R 21 , —CF 3 , —CN, —NO 2 , —N 3 , —C(O)R 20 , —C(O)OR 20 , —C(O)NR 20 R 21 , acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, aliphatic, substituted aliphatic, aryl or substituted aryl; alternatively two R 13 groups together with the atoms to which they are attached and any intervening atoms may form an additional optionally substituted, 3, 4, 5, 6 or 7 membered ring; and,
each R 16 , R 17 and R 18 is independently hydrogen, halogen, aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl or substituted heteroaryl;
alternatively two R 13 , R 14 , R 15 , R 16 , R 17 and R 18 groups together with the atoms to which they are attached, and any intervening atoms may form an optionally substituted 3, 4, 5, 6 or 7 membered ring; and,
alternatively when two R 13 , R 14 , R 15 , R 16 , R 17 and R 18 groups are attached to a carbon atom, together said two groups and said carbon atom may form a carbonyl or an optionally substituted vinyl group.
8. A compound according to claim 1 , wherein q is 1.
9. A compound according to claim 1 , wherein R 2 is selected from Table C:
TABLE C
wherein R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 are as defined above;
alternatively, R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 groups together with the atoms to which they are attached, and any intervening atoms may form an optionally substituted 3, 4, 5, 6 or 7 membered ring;
alternatively when two R 13 , R 14 , R 15 , R 16 , R 17 and R 18 groups are attached to a carbon atom, together said two groups and said carbon atom may form a carbonyl or an optionally substituted vinyl group;
u and w is independently 0, 1, 2, 3, 4, 5 or 6; and,
Cy3 is optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl.
10. A compound according to claim 1 , wherein R 3 is selected from Table D, or R 3a selected from Table E:
TABLE D
TABLE E
11. A compound of claim 1 , wherein each G 1 and G 2 is independently —CH 2 —.
12. A compound of claim 1 , wherein each R 27 and R 29 is independently hydrogen.
13. A compound of claim 5 , wherein R 1 is selected from methyl, ethyl, propyl, cyclopropyl, isopropyl, n-butyl, tert-butyl, cyclobutyl, n-pentyl, neopentyl, cyclopentyl, n-hexyl and cyclohexyl.
14. A compound selected from Table 1A or a pharmaceutically acceptable salt, ester or prodrug thereof:
TABLE 1A
1
2
4
6
7
8
9
10
11
12
13
14
16
17
18
19
20
21
23
24
25
26
27
28
29
30
32
34
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
15. A method of treating a disease related to a defect in isocitrate dehydrogenase comprising the step of administering a compound of Formula I to a patient in need thereof:
each n and m is independently 0, 1, 2 or 3;
each p and q is independently 0, 1, 2, 3, 4, 5, 6 or 7;
X 1 is —C(O)N(R A )—, —C(S)N(R A )—, or —S(O) 2 N(R A )—;
wherein R A is hydrogen, aliphatic, substituted aliphatic, heteroaryl, substituted heteroaryl, aryl or substituted aryl;
X 2 is —S— —O—, —S(O) 2 —, —C(R 20 )(R 21 )— or —N(R B )—;
wherein R B is hydrogen, aliphatic, substituted aliphatic, heteroaryl, substituted heteroaryl, aryl or substituted aryl;
each R 1 and R 2 is independently hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl;
each R 10 is independently absent, hydrogen, halogen, —OR 20 , —SR 20 , —NR 20 R 21 , —CF 3 , —CN, —NO 2 , —N 3 , —C(O)OR 20 , —C(O)R 20 , —C(O)NR 20 R 21 , acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, aliphatic, substituted aliphatic, aryl or substituted aryl; alternatively two of R 10 groups together with the atoms to which they are attached and any intervening atoms may form an additional optionally substituted, 3, 4, 5, 6 or 7 membered ring;
wherein each R 20 and R 21 is independently hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl;
each R 11 is independently absent, hydrogen, halogen, —OR 20 , —SR 20 , —NR 20 R 21 , —CF 3 , —CN, —NO 2 , —N 3 , —C(O)OR 20 , —C(O)R 20 , —C(O)NR 20 R 21 , acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, aliphatic, substituted aliphatic, aryl or substituted aryl; alternatively two of R 11 groups together with the atoms to which they are attached and any intervening atoms may form an additional optionally substituted, 3, 4, 5, 6 or 7 membered ring; and, Cy1 is an optionally substituted aryl or optionally substituted heteroaryl.
16. The method according to claim 15 , wherein said defect in isocitrate dehydrogenase is a somatic mutation at codon 132 isocitrate dehydrogenase (IDH1) or at codon 172 in isocitrate dehydrogenase 2 (IDH2) or at codon 140 of IDH2.
17. The method according to claim 15 , wherein said patient has mutations on both IDH1 and IDH2.
18. The method according to claim 15 , wherein said mutation is selected from R132H, R132C, R132S, R132L, R132G in IDH1, or R172M, R172G, R172K or R140Q in IDH2.
19. The method according to claim 15 , wherein said disease is a cell proliferative disease.
20. The method according to claim 15 , wherein said disease is selected from Grade I, II, III or IV glioma.
21. The method according to claim 15 , wherein said disease is selected from astrocytomas, oligodendrogliomas, ependymomas and glioblastoma multiforme (GBM).
22. The method according to claim 15 , wherein said disease is associated with an increase in the production of 2-hydroxyglutarate in a tissue or plasma.
23. The method according to claim 15 , wherein said compound of Formula I is a compound of Formula IA, IB, IC or ID, or a pharmaceutically acceptable salt, ester or prodrug thereof:
wherein each n and m is independently 0, 1, 2 or 3;
each p and q is independently 0, 1, 2, 3, 4, 5, 6 or 7;
X 1 is —C(O)N(R A )—;
wherein R A is independently hydrogen, aliphatic, substituted aliphatic, heteroaryl, substituted heteroaryl, aryl or substituted aryl;
X 2 is —S— —O—, —S(O) 2 — —C(R 20 )(R 21 )— or —N(R B )—;
wherein R B is independently hydrogen, aliphatic, substituted aliphatic, heteroaryl, substituted heteroaryl, aryl or substituted aryl;
each R 1 and R 2 is independently hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl;
R 3 is hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl;
each R 10 , and R 28 is independently absent, hydrogen, halogen, —OR 20 , —SR 20 , —NR 20 R 21 , —CF 3 , —CN, —NO 2 , —C(O)OR 20 , —C(O)R 20 , —C(O)NR 20 R 21 , acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, aliphatic, substituted aliphatic, aryl or substituted aryl; alternatively two of R 10 groups together with the atoms to which they are attached and any intervening atoms may form an additional optionally substituted, 3, 4, 5, 6 or 7 membered ring;
wherein each R 20 and R 21 is independently hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl;
each R 11 is independently absent, hydrogen, halogen, —OR 20 , —SR 20 , —NR 20 R 21 , —CF 3 , —CN, —NO 2 , —N 3 , —C(O)R 20 , —C(O)OR 20 , —C(O)NR 20 R 21 , acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, aliphatic, substituted aliphatic, aryl or substituted aryl; alternatively two of R 11 groups together with the atoms to which they are attached and any intervening atoms may form an additional optionally substituted, 3, 4, 5, 6 or 7 membered ring;
each G 1 and G 2 is independently, absent, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl;
each R 27 and R 29 is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
wherein R 3 a is selected from alkyl, aryl, alkyl substituted with aryl, straight chain or branched C 1 -C 10 alkyl, C 1 -C 10 alkenyl, C 1 -C 10 alkynyl, C 1 -C 10 alkoxy, alkoxyC 1 -C 10 alkoxy, C 1 -C 10 alkylamino, alkoxyC 1 -C 10 alkylamino, C 1 -C 10 alkylcarbonylamino, C 1 -C 10 alkylaminocarbonyl, aryloxyC 1 -C 10 alkoxy, aryloxyC 1 -C 10 alkylamino, aryloxyC 1 -C 10 alkylamino carbonyl, C 1 -C 10 -alkylaminoalkylaminocarbonyl, C 1 -C 10 alkyl(N-alkyl)aminoalkyl-aminocarbonyl, alkylaminoalkylamino, alkylcarbonylaminoalkylamino, alkyl(N-alkyl)aminoalkylamino, (N-alkyl)alkylcarbonylaminoalkylamino, alkylaminoalkyl, alkylaminoalkylaminoalkyl, alkylpiperazinoalkyl, piperazinoalkyl, alkylpiperazino, alkenylaryloxyC 1 -C 10 alkoxy, alkenylarylaminoC 1 -C 10 alkoxy, alkenylaryllalkylamino C 1 -C 10 alkoxy, alkenylaryloxyC 1 -C 10 alkylamino, alkenylaryloxyC 1 -C 10 alkylaminocarbonyl, piperazinoalkylaryl, heteroarylC 1 -C 10 alkyl, heteroarylC 1 -C 10 alkenyl, heteroarylC 1 -C 10 alkynyl, heteroarylC 1 -C 10 alkylamino, heteroarylC 1 -C 10 alkoxy, heteroaryloxyC 1 -C 10 alkyl, heteroaryloxyC 1 -C 10 alkenyl, heteroaryloxyC 2 -C 10 alkynyl, heteroaryloxyC 1 -C 10 alkylamino, heteroaryloxyC 1 -C 10 alkoxy;
Cy1 is an optionally substituted aryl or optionally substituted heteroaryl; and,
R 40 is selected from:
wherein, R 41 is hydrogen, halogen, aliphatic, substituted aliphatic, aryl, substituted aryl, —OR 20 , —SR 20 , —NR 20 R 21 , —CF 3 , —CN, —NO 2 , —C(O)R 20 , —C(O)OR 20 , —C(O)NR 20 R 21 , acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl.
24. The method according to claim 15 , wherein said compound of Formula I is selected from Table 1:
TABLE 1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
25. A method of treating a patient exhibiting abnormal 2-hydroxyglutarate (2-HG) production comprising administering a compound according to claim 1 .
26. The method according to claim 25 , wherein said abnormal 2-HG production is an increase of more than about 20 fold, or more than about 40 fold or more than about 50 fold or more than about 100 fold or more than about 200 fold compared to a corresponding normal cell or tissue or plasma concentration of 2-HG.
27. The method according to claim 26 , wherein said increase is due to a mutation in IDH1.
28. The method according to claim 26 , wherein said increase is due to a mutation in IDH2.
29. A method of treating a disease related to a defect in isocitrate dehydrogenase comprising the step of administering a compound according to claim 1 to a patient in need thereof, wherein said compound has a selectivity for inhibition of a mutant of IDH1 or a mutant of IDH2.
30. The method according to claim 29 , wherein the ratio of inhibitory activity against an IDH1 mutant over the wild type IDH1 is about 2 to about 1000.
31. The method according to claim 23 , wherein the ratio of inhibitory activity against an IDH2 mutant over the wild type IDH2 is about 2 to about 1000.
32. The method according to claim 30 , wherein the ratio of inhibitory activity against an IDH1 mutant over the wild type IDH1 is about 5 to about 500.
33. The method according to claim 30 , wherein the ratio of inhibitory activity against an IDH1 mutant over the wild type IDH1 is about 10 to about 100.
34. The method according to claim 30 , wherein the ratio of inhibitory activity against an IDH1 mutant over the wild type IDH1 is about 25 to about 100.
35. The method according to claim 31 , wherein the ratio of inhibitory activity against an IDH2 mutant over the wild type IDH2 is about 5 to about 500.
36. The method according to claim 31 , wherein the ratio of inhibitory activity against an IDH2 mutant over the wild type IDH2 is about 10 to about 100.
37. The method according to claim 31 , wherein the ratio of inhibitory activity against an IDH2 mutant over the wild type IDH2 is about 25 to about 100.
38. A method of treating a cell proliferative disease comprising the step of administering a compound according claim 1 to a patient in need thereof.
39. The method according to claim 38 , wherein said cell proliferative disease is cancer.
40. The method according to claim 39 , wherein said cancer is selected from glioma, acute myeloid leukemia (AML), Burkitt's leukemia/lymphoma (B-ALL), melanoma and prostate carcinoma.
41. The method according to claim 40 , wherein said glioma is selected from astrocytomas, oligodendrogliomas, ependymomas and glioblastoma multiforme.
42. The method according to claim 38 , wherein said compound is an inhibitor of a mutant of IDH1 wherein said mutation is selected from R132H, R132C, R132S, R132L, R132G in IDH1.
43. The method according to claim 38 , wherein said compound is an inhibitor of a mutant of IDH2, wherein said mutation is selected from R172M, R172G, R172K or R140Q.
44. The method according to claim 38 , wherein said compound is an inhibitor of wild type IDH1.
45. The method according to claim 38 , wherein said compound is an inhibitor of wild type IDH2.
46. A compound of claim 23 , wherein each G 1 and G 2 is independently —CH 2 —.
47. A compound of claim 23 , wherein each R 27 and R 29 is independently hydrogen.Cited by (0)
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